Most of medicines that have been recently developed and commercially available are chiral products. This is attributed to side effects or decreased efficacies caused by racemic drugs. Therefore, in order to increase both the safety and the efficacy, studies to develop chiral drugs containing optically pure stereoisomers has been widely attempted. In the chiral drugs, high chemical purity and high optical purity are required for ensuring the safety and the efficacy.
Carvedilol (IUPAC NAME: 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol) is a compound having formula 1:

wherein, * represents a chiral center.
As shown in the formula 1, the carvedilol has one chiral center, and may exist in either (R)-isomer or (S)-isomer. Herein, as a blocker of α1-adrenoreceptor, (R)-isomer and (S)-isomer exhibit almost the same activities. To the contrary, as a blocker of β1-adrenoreceptor, (S)-isomer has an enhanced, superior activity to (R)-isomer [EP 127,099; Chirality 1989, 1, 265; J. Pharm. Exp. Ther., 1992, 263, 92; Clin. Pharmacokin., 1994, 26, 335; Cardiovasc. Res., 1994, 28, 400; J. of Chromatography B. 1996, 682, 349]. Further, the carvedilol is now used as an antioxidant, anti-inflammatory agent, anti-apoptotic agent [The American Journal of Cardiology, 2004, 93(9A), 3B]. For these reasons, provision of a process for the efficient preparation of highly optical pure chiral carvedilol in an economic manner is an important task to the development of various drugs comprising the chiral carvedilol.
Conventional processes for the preparation of the chiral carvedilol are shown in a reaction scheme 1:

wherein, R represents hydrogen or a benzyl group.
As shown in the reaction scheme 1, the targeted carvedilol was prepared from ring opening of a chiral epoxy-carbazole of formula 3 with an ethylamine compound of formula 4 [R=hydrogen, U.S. Pat. Nos. 4,503,067 and 4,697,022]. However, the process leads to formation of a bis-substituted side product that is not easy to be removable in the purification procedure. The process requires an extraordinary purification procedure, thereby hindering the preparation of highly optical pure carvedilol. Furthermore, loss of the targeted carvedilol is inevitable in the purification procedure, which results in significant decrease of the yield of the carvedilol.
In order to avoid the disadvantage resulted from the bis-substituted side product, other attempts have been performed. In order to prevent the formation of the bis-substituted side product, a N-protected compound of formula 4 (R=benzyl) was used as a starting material in the reaction scheme 1 and applied to ring opening of a chiral epoxy compound of formula 3 [R=benzyl, EP 918,055]. The process produces no bis-substituted side product. However, it suffered from the disadvantage that an expensive palladium catalyst should be used in order to deprotect the benzyl group.
As an alternative, the ethylamine compound of formula 4 was used in an excess over the compound of formula 3 to reduce the formation of the bis-substituted side product [R=hydrogen, WO 02/00216]. Even though the process could reduce the formation of the bis-substituted side product, there still remain problems caused from small amount of the bis-substituted side product. In addition, the process suffered from low price competitiveness due to excess use of the expensive ethylamine compound.
In addition, the ethylamine compound of formula 4 or its benzylated form undergoes degradation by exposure to air and light. Therefore, the compound of formula 4 has a limitation to the application to mass production. In order to overcome the disadvantage, acid addictive salt of the ethylamine compound of formula 4 (R═H) was used as a starting material in the ring opening reaction with the compound of formula 3 to increase the stability [WO 2004/041783]. The process has an advantage applicable to mass production of the chiral carvedilol. Nonetheless, it suffered from the formation of the bis-substituted side product and from excess use of the ethylamine compound.
In order to avoid the formation of the bis-substituted side product, new attempt has been tried.
The amine group of the compound of formula 4 was firstly protected with a benzyl group, and a chloro-propaiionyl group was introduced thereto. The obtained product was alkylated with a 9H-4 hydroxy carbazole of formula 8, followed by a reduction step and a debenzylation step to produce the carvedilol (Korean Published Patent No. 2005-0003764). However, the process requires a strong reducing agent such as sodium borohydride or lithium borohydride and an expensive palladium catalyst.
Further another process for the preparation of the carvedilol known in the art comprises reacting the amine compound of formula 4 with a carbonated compound to produce a carbamate having two leaving groups, followed by cyclization reaction to produce a oxazolidinone compound that is used as an intermediate for the synthesis of the carvedilol [EP 1,282,601 and 1,367,052]. In the process, the oxazolidinone compound was alkylated with 9H-4-hydroxy carbazole and deprotected to produce the carvedilol.
Even though the above two processes effectively inhibits the formation of the bis-substituted side product, they are not suitable for the production of chiral carvedilol.
As mentioned in the above, the conventional methods had one or more unresolved technical problems for the application to mass production of highly optical pure chiral carvedilol. Therefore, an efficient process for the preparation of highly optical pure chiral carvedilol is now urgently demanded.